Submissions for variant NM_024422.6(DSC2):c.1994A>G (p.Asp665Gly)

dbSNP: rs778236763

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770532	SCV000901979	uncertain significance	Cardiomyopathy	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770532	SCV001354432	uncertain significance	Cardiomyopathy	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 665 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001364362	SCV001560506	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 665 of the DSC2 protein (p.Asp665Gly). This variant is present in population databases (rs778236763, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 626836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003166036	SCV003853613	uncertain significance	Cardiovascular phenotype	2022-11-21	criteria provided, single submitter	clinical testing	The p.D665G variant (also known as c.1994A>G), located in coding exon 13 of the DSC2 gene, results from an A to G substitution at nucleotide position 1994. The aspartic acid at codon 665 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.